Process for the preparation of iopamidol and the new intermediated therein

ABSTRACT

A process for the preparation of (S)-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxo-propyl)amino]-2,4,6-triiodo-1,3-benzendicarboxamide (iopamidol) starting from 5-amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamide (II) which process comprises a) reacting the compound of formula (II) with a suitable protecting agent, to give a compound of formula (III) wherein R is a group of formula A or B wherein R 1  is a hydrogen atom, a C 1 ÷C 4  straight or branched alkoxy group, R 2  is hydrogen, a C 1 ÷C 4  straight or branched alkoxy group and R 3 ?is a C 1 ÷C 4  straight or branched alkyl group, a trifuoromethyl or a trichloromethyl group; b) acylating the amino group in position 5 of the intermediate compound of formula (III), by reaction with a (S)-2-(acetyloxy)propanoyl chloride to give a compound of formula (IV) wherein R is as defined above; and c) removing all the acyl groups present in the compound of formula (IV) under basic conditions, with prior cleavage of the cyclic protections of the hydroxy groups in the carboxamido substituents under acidic conditions, when R is a group of formula A carboxamido hydroxy groups under acidic conditions. The invention also refers to the new intermediates of formula (III) and (IV) wherein —R is a group A.

This application is the national stage filing of correspondinginternational application number PCT/EP01/13939, filed Nov. 29, 2001,which claims priority of Italian application MI2000A002601, filed Dec.1, 2000.

present invention relates to a new process for the preparation ofiopamidol (i.e.(S)-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide)starting from the corresponding 5-unsubstitued amino derivative and tothe new intermediates obtained in said process.

BACKGROUND OF THE INVENTION

(S)-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamideof formula (I).

which is known as Iopamidol, is one of the most widely employednon-ionic radiographic contrast agents in the world.

It was first described in GB1472050, where its synthesis by the processoutlined in the following Scheme has been reported:

The above process, that is still widely employed industrially, hasanyway several drawbacks.

One of them is the introduction of the protected chiral synton(S)-2-(acetyloxy)propanoyl on the 5-amino group at an early stage of theoverall process, i.e. before the amidation with 2-amino-1,3-propanediol.

Just introducing this chiral group via reaction of the5-amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamidewith (S)-2-(acetyloxy)propanoyl chloride would lead to the preferentialacylation of the more reactive hydroxy groups of the carboxamidosubstituents, thus causing remarkable wasting of expensive reactant.

WO 00/50385 has recently described a process for the preparation ofpolyhydroxy compounds (including i.a. iopamidol) comprising the step ofdeacylating, under acidic conditions, an acylated compound having theformula:

wherein R₄ and R₅ are optionally acylated dihydroxyalkyl groups, R₆ isalkyl and R₃ is i.a. a methyl group.

According to WO 00/50385 the acid used in this deacylation reaction isthen removed by batch treatment with an acid scavenging resin; anaqueous solution of the thus obtained product is purified by passingthrough a non-ionic polymeric adsorbent resin; the eluate isconcentrated to an oil; and the oil is crystallised fromacetonitrile/ethanol or ethanol.

The above method is said to reduce racemization at the chiral carbonthat—according to WO 00/50385—occurs whenever basic conditions areemployed to remove the R₆CO— protecting group of the chiral substituent.

Examples of acyl groups reported in WO 00/50385 are formyl, acetyl,propanoyl, butanoyl, pivaloyl, pentanoyl, trifluoroacetyl, and benzoyl.

For iopamidol, WO 00/50385 describes the preparation of the startingacylated compound through introduction of the R₆CO— protected chiralsubstituent on the 5-amino group of a tetraester of the5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide. The isolatedpentacylated product is then converted into iopamidol by the claimedprocess that requires deacylation under drastic acidic conditions. Moreparticularly the actual conditions exemplified in WO 00/50385 foriopamidol are heating the pentacetyl derivative at the refluxtemperature with hydrochloric acid in methanol for 30 hours.

SUMMARY OF THE INVENTION

It has now been found, and represents a first object of the presentinvention, that it is possible to carry out the deacylation of apentacylated iopamidol, under basic conditions getting a final product,iopamidol, that has an extremely high optical purity.

Furthermore, it has been found that according to the process of thepresent invention it is not necessary to isolate the pentacylatedproduct;

more particularly, it has been found that introducing the(S)-2-(acetyloxy)propanoyl substituent onto the 5-amino group of aN,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamidewherein the hydroxy groups of the carboxamido substituents have beensuitably acylated and then removing all the acyl groups under basicconditions without isolating the intermediate product, the overallprocess does proceed with very high yield.

Finally, it has been found that the process according to the presentinvention can be employed, with some modification, also when protectionof the hydroxy groups of the carboxamido substituents is achieved byconversion of these groups into optionally 2-monosubstituted or2,2-disubstituted N,N′-bis(1,3-dioxan-5-yl)carboxamides.

The new intermediates 5-amino-N,N′-bis(optionally 2-monosubstituted or2,2-disubstituted-1,3-dioxan-2-yl)-2,4,6-triiodo-1,3-benzenecarbox-amides(III) as well as the (S)-N,N′-bis(optionally 2-monosubstituted or2,2-disubstituted-1,3-dioxan-2-yl)-5-[2-acetoxy-1-(oxopropyl)amino]-2,4,6-triiodo-1,3-benzenecarboxamides(IV) represent a further specific object of the present invention.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

A first object of the present invention is therefore a process for thepreparation of iopamidol (I)

starting from the compound of formula (II)

which process comprises

-   a) reacting the compound of formula (II) with a suitable protecting    agent, to give a compound of formula (III)

wherein —R is a group of formula A or B

wherein R₁ is a hydrogen atom, a C₁÷C₄ straight or branched alkyl groupor a C₁÷C₄ straight or branched alkoxy group, R₂ is a hydrogen atom, aC₁÷C₄ straight or branched alkyl group or a C₁÷C₄ straight or branchedalkoxy group and R₃ is a C₁÷C₄ straight or branched alkyl group, atrifluoromethyl, or a trichloromethyl group;

-   b) acylating the amino group in position 5 of the intermediate    compound of formula (III), by reaction with a    (S)-2-(acetyloxy)propanoyl chloride to give a compound of formula    (IV)

wherein R is as defined above; and

-   c) removing all the acyl groups present in the compound of    formula (IV) under basic conditions, with prior cleavage of the    cyclic protections of the hydroxy carboxamido substituents under    acidic conditions when R is a group of formula A.

The compound of formula (II) is a known product and its preparation canbe carried out by any of the known methods, such as those described inGB 1472050, CH 627653 or U.S. Pat. No. 5,278,311.

According to step a) of the process of the present invention thecompound (II) is reacted with a compound which is suitably selectedamong aldehydes, ketones (possibly in the corresponding acetal or ketalrelated forms), orthoesters, or anhydrides, depending on the type ofprotecting group to be introduced.

For instance when —R in the compounds (III) represents a group offormula A, the compound (II) will be reacted with adi-(C₁–C₄)alkoxy-methane when both R₁ and R₂ are hydrogen, with thesuitably selected aldehydes or ketones of formula R₁COR₂ (possibly inthe corresponding acetal or ketal related forms) in the presence of asmall amount of a tri-(C₁–C₄)alkyl orthoformate as dehydrating agentwhen R₁ is a hydrogen atom or a C₁÷C₄ straight or branched alkyl groupand R₂ is a C₁÷C₄ straight or branched alkyl group or with orthoestersof formula R₁C(R₂)₃ when at least R₂ is an alkoxy group.

When, on the other hand, —R in the compounds (III) represents a group offormula B, said group is typically introduced by reacting the compound(II) with the suitably selected anhydride of formula (R₃CO)₂O.

When —R in the compounds (III) represents a group of formula A,preferred compounds are those wherein both R₁ and R₂ are C₁÷C₄ straightor branched alkyl groups; more preferred are those wherein both R₁ andR₂ are C₁÷C₄ straight alkyl groups; and even more preferred are thosewherein both R₁ and R₂ are methyl.

Another group of preferred compounds (II) wherein —R represents a groupA are those wherein R₁ is hydrogen and R₂ is a C₁÷C₄ straight alkoxygroup.

When —R in the compounds (III) represents a group of formula B,preferred compounds are those wherein R₃ represents a C₁÷C₄ straight orbranched, alkyl group; more preferred are those wherein R₃ represents aC₁÷C₄ straight alkyl group; even more preferred are those wherein R₃ ismethyl.

The reaction of step a) is carried out in the presence of an organicsolvent selected from the dipolar organic solvents, e.g.N,N-dimethylformamide, N,N-dimethylacetamide, andN-methyl-2-pyrrolidone, the inert aprotic organic solvents, and themixtures thereof.

The reaction is carried out using at least the stoichiometric amount ofthe reactants but preferably at least a slight excess of the reactantintroducing the protecting group with respect to the starting compound(II).

Needless to say that if a compound of formula (III) is desired wherein—Ris a group A, at least two mol of the corresponding aldehyde or ketone(also in the form of the corresponding acetal or ketal) or orthoesterhave to be employed per mol of starting compound (II); while when acompound (III) is desired wherein —R is a group B then at least four molof the corresponding anhydride must be used. In both cases, however, atleast a slight excess, e.g. at least an excess of about 5% by mol overthe stoichiometric amount is typically employed, a molar excess of up toabout 50% being preferred.

The reaction is typically carried out at room temperature but lower orhigher temperatures may as well be employed. As an example, temperaturesin the range of from about 5° C. to about 60° C. proved to be suitablefor step a).

The introduction of the protecting group in step a) is preferablycarried out under slightly different reaction conditions depending onthe particular reactant employed. The person skilled in the art will beaware of these differences and will be able to optimise the reactionconditions on the basis of his personal knowledge.

As an example, when in the compound (III) —R is a group of formula A,then step a) in the above process will be preferably carried out in thepresence of an acidic catalyst. More particularly the reaction will bepreferably carried out in the presence of from about 0.1 to about 2 molof an acid per mol of compound of formula (II). Suitable acids that canbe employed in this step are for instance sulfuric acid, hydrochloricacid, methanesulfonic acid, p-toluenesulfonic acid, or carboxylic acids,such as formic acid, acetic acid, or propionic acid.

For the preparation of the most preferred compound of formula (III)wherein —R is an A group wherein R₁ and R₂ are both methyl groups, thepreferred reactant is acetone in the presence of a small amount of atri(C₁÷C₄)alkyl orthoformate or 2,2-dimethoxypropane, while for thepreparation of the compounds of formula (III) wherein —R is an A groupwherein R₁ is hydrogen and R₂ is a C₁÷C₄ straight alkoxy group, thepreferred reactants are the corresponding tri-(C₁÷C₄) straight alkylorthoformates.

In the actual practice, in the above case, the reaction will bepreferably carried out by dripping a mixture of an excess over thestoichiometric of the suitably selected ketone/ketal or orthoformatetogether with a catalytic amount, typically about 0.1 mol per mol ofcompound of formula (II), of a strong acid, preferably sulfuric ormethanesulfonic acid, into a solution of the compound of formula (II) ina dipolar aprotic solvent, typically N,N-dimethylacetamide.

Once the reaction, that may take from few minutes to 30 hours to becomplete, is over, the protected compound of formula (III) wherein —R isa group of formula A is isolated, through neutralisation of the acidiccatalyst, precipitation of the desired compound (III) by the addition ofa diluted (generally 3% by weight) solution of bicarbonate, andpurification of the precipitate by crystallisation from ethanol andwater.

On the other hand, when in the compound (III) —R is a group of formulaB, then step a) in the above process will be preferably carried out inthe presence of a catalyst. More particularly it will be generallycarried out in the presence of a small catalytic amount (typically from5×10⁻⁴ to 5×10⁻¹ mol per mol of starting compound (II)) of4-(dimethylamino)pyridine. The reaction solvent may be selected—asindicated above—among the dipolar aprotic organic solvents, the inertnon hydroxylated organic solvents and the mixtures thereof. When —R is agroup B, also weakly basic organic solvents, such as pyridine, may beemployed.

In the actual practice the reaction to get the compounds of formula(III) wherein —R is a compound of formula B will be preferably carriedout by dripping a mixture of an excess over the stoichiometric of thesuitably selected anhydride (R₃CO)₂O and a catalytic amount, typicallyfrom 0.01 to 0.1 mol per mol of compound of formula (II), of4-(dimethylamino)pyridine in a solution of the starting compound offormula (III) in N,N-dimethylacetamide. The 4-(dimethylamino)pyridinemay be added to the reaction mixture as such or supported on a resin.

Once the reaction, that typically may take from a couple of hours to oneday, depending on the reaction conditions employed, is complete, theprotected compounds of formula (III) wherein —R is a group of formula Bare precipitated from the reaction mixture by dilution with water or/andethanol and isolated by filtration.

Step b) in the overall process outlined above consists in the acylationreaction of the primary amino group of the compounds of formula (III),with at least 1 mol of (S)-2-(acetyloxy)propanoyl chloride to give thecompounds of formula (IV).

The reaction is usually carried out in an inert dipolar aprotic solventsuch as N,N-dimethylacetamide, N,N-dimethylformamide,1-methyl-2-pyrrolidone and the like solvents and in presence of an acid.

Acids that can suitably be employed in step b) are for instancehydrohalic acid that can easily be introduced into the reaction mixtureas the hydrohalide salts of the dipolar aprotic solvents employed, suchas the N,N-dimethylacetamide hydrochloride or—preferably—by bubbling theanhydrous hydrogen chloride gas into the reaction mixture.

The acid is typically employed in an amount of from about 0.1 to about0.4 mol per mol of product of formula (III).

The temperature for this step of the reaction is generally comprisedbetween about 5 and about 60° C.

Preferably, however, the reaction is carried out at room temperature ora temperature slightly above room temperature (about 45–50° C.).

The reaction of step b) is typically complete in a time comprisedbetween about 2 and about 20 hours, depending on the solvent employedand the reaction conditions adopted.

In the following step c) all the acyl groups which are present in theintermediate compound of formula (IV) are removed under basicconditions, with prior cleavage of the cyclic protections under acidicconditions when R is a group of formula A.

In particular when a compound (IV) is employed wherein —R is a group offormula A, the basic hydrolysis to remove the acetyl protecting group ofthe 5-[(2-hydroxy-1-oxopropyl)amino] is preceded by cleavage of thecyclic protections of the carboxamido hydroxy groups under acidicconditions.

When on the other hand a compound (IV) is employed wherein —R is a groupof formula B, all the acyl groups, i.e., the acetyl protecting group ofthe 5-[(2-hydroxy-1-oxopropyl)amino] substituent as well as the fourR₃CO-groups, are removed in one single step under basic conditions.

The basic hydrolysis is carried out typically in water or in a mixtureof water and an organic solvent miscible therewith such as a C₁÷C₄straight or branched alkanol, or a dipolar aprotic organic solvent suchas N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone,and the like solvents.

The pH of the reaction mixture is maintained between 10 and 11 by theaddition of a strong inorganic base such as NaOH or KOH, typically as anaqueous solution thereof. The reaction is preferably carried out at roomtemperature but temperatures of from about 10° C. to about 60° C. provedto be useful.

As indicated above, when in the compound of formula (IV) —R is a groupof formula A, the basic hydrolysis of the acetyl group has to bepreceded by the cleavage of the cyclic protections of the hydroxy groupsof the carboxamido substituents under acidic conditions.

This is easily achieved by the addition of a strong cation exchangeresin, preferably Duolite C20 MB, Amberlite IR120 or Amberjet 1200 (Rohm& Haas) or of an aqueous solution of a strong mineral acid, e.g.hydrochloric or sulfuric acid, to a solution of the compound of formula(IV) wherein —R is a group A, in water or in a mixture of water and anorganic solvent miscible therewith such as a C₁÷C₄ straight or branchedalkanol, or a dipolar aprotic organic solvent such asN,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone,and the like solvents.

The amount of acid required in this step is comprised between about 0.2and about 0.4 mol of acid per mol of compound of formula (IV) wherein —Ris a group A. The reaction is preferably carried out at a temperatureslightly above room temperature, e.g. comprised between about 40° C. andabout 55° C., and is typically complete in 2 to 5 hours depending on thereaction conditions employed.

The hydrolysis under basic conditions to yield the end iopamidol is thenjust obtained by adding an aqueous solution of NaOH or KOH directlythereto in such an amount to keep the pH between about 10 and about 11.

The isolation of the product of formula (I) from the basic aqueoussolution thus obtained, is usually carried out by passing the solutionon a system of ionic exchange resins and optionally through ananofiltration unit, as described for example in U.S. Pat. No. 5,811,581or EP-A-888,190, followed by crystallization of the product (I) from alower alkanol, as described for instance in U.S. Pat. No. 5,571,941.

A further specific object of the present invention are the intermediatecompounds of formula (III) and (IV), wherein —R is a group of formula A

wherein R₁ is a hydrogen atom, a C₁÷C₄ straight or branched alkyl groupor a C₁÷C₄ straight or branched alkoxy group, and R₂ is hydrogen, aC₁÷C₄ straight or branched alkyl group or a C₁÷C₄ straight or branchedalkoxy group.

Preferred among the compounds of formula (III) and (IV) wherein —R is agroup A are those wherein R₁ and R₂ are C₁÷C₄ straight or branched alkylgroups; more preferred are those wherein both R₁ and R₂ are C₁÷C₄straight alkyl groups; and even more preferred are those wherein both R₁and R₂ are methyl.

Another group of preferred compounds (III) and (IV) wherein —Rrepresents a group A are those wherein R₁ is hydrogen and R₂ is a C₁÷C₄straight alkoxy group.

The following examples are only aimed at further illustrating thepresent invention in some of its preferred embodiments but should not beinterpreted as a limitation to the scope thereof.

EXAMPLE 1 Preparation of5-amino-N,N′-bis(2,2-dimethyl-1,3-dioxan-5-yl)-2,4,6-triiodo-1,3-benzenedicarboxamide((III): —R=a group A wherein R₁ and R₂=methyl)

2,2-Dimethoxypropane (9.5 mL, 77.8 mmol) and 98% sulfuric acid (0.25 g,2.6 mmol) are dripped into a 0.5 L vessel containing a solution of thecompound of formula (II) (18.3 g, 25.9 mmol) (prepared as described inGB1472050) in dimethylacetamide (90 mL) stirred at room temperature.After 20 hours under stirring the solution is neutralised with NaHCO₃and concentrated under vacuum. Acetone (250 mL) and 3% aq. NaHCO₃ (50mL) are then added to the obtained oily residue and the solid isrecovered by filtration and crystallized from 70% ethanol to give thecompound of the title (13 g, 16.5 mmol after drying).

Yield: 64% The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with theindicated structure.

EXAMPLE 2 Preparation of5-amino-N,N′-bis(2-ethoxy-1,3-dioxan-5-yl)-2,4,6-triiodo-1,3-benzenedicarboxamide((III): —R=a group A wherein R₁ is hydrogen and R₂ is ethoxy)

Methanesulfonic acid (0.27 g, 2.8 mmol) and triethyl orthoformate (9.25g, 62.4 mmol) are dripped in 1 hour into a solution of the compound offormula (II) (20 g, 28.4 mmol) (prepared as described in GB1472050) inN,N-dimethylacetamide (150 mL) stirred at 25° C. After 1 hour thesolution is neutralised with NaHCO₃. The solvent is evaporated undervacuum and the oily residue is taken up with aq. 5% NaHCO₃ (300 mL).

The solid thus obtained is filtered and crystallized twice from 70%ethanol to afford the compound of the title (14.7 g, 18.7 mmol).

Yield: 66% The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with theindicated structure.

EXAMPLE 2 BIS Alternative preparation of5-amino-N,N′-bis(2-ethoxy-1,3-dioxan-5-yl-2,4,6-triiodo-1,3-benzenedicarboxamide((III): —R=a group A wherein R₁ is hydrogen and R₂ is ethoxy)

Triethyl orthoformate (18.6 g, 125.5 mmol) is added over 3 min to asolution of the compound of formula (II) (40 g, 57 mmol) andmethanesulfonic acid (0.55 g, 5.7 mmol) in N,N-dimethylacetamide (400mL), stirred at room temperature. After 15 min, the reaction mixture isneutralized with 1 M NaOH (5.7 mL, 5.7 mmol) and N,N-dimethylacetamideis distilled to give an oily residue. The latter is poured into 1% aq.NaHCO₃ causing the formation of a white precipitate that, after 15 hunder stirring, is recovered by filtration, washed with H₂O and dried.The solid is then suspended in absolute ethanol (600 mL), refluxed for 3hours and allowed to cool to room temperature. The solid is recovered byfiltration, washed with EtOH (30 mL) and dried to afford the compound ofthe title (40 g, 48.95 mmol) as a white solid.

Yield: 86%. The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with theindicated structure.

EXAMPLE 3 Preparation ofN,N′-bis[2-acetyloxy-1-[(acetyloxy)methyl]ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide((III): —R is a group B where R₃ is methyl)

Acetic anhydride (9 mL, 95 mmol) is dripped into a suspension of thecompound of formula (II) (7 g, 10 mmol) (prepared as described inGB1472050) in pyridine (40 mL) stirred at 25° C. After 3 hours, thesolution obtained is added dropwise to deionized water (0.3 L) and theprecipitate is recovered by filtration, washed with 5% acetic acid, thenwith deionized water, and finally dried under vacuum at the temperatureof 40° C. for 12 hour to obtain the compound of the title (7.86 g, 9mmol).

Yield: 90% The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with theindicated structure.

EXAMPLE 3 BIS Alternative preparation ofN,N′-bis[2-acetyloxy-1-[(acetyloxy)methyl]ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide((III): —R is a group B where R₃ is methyl)

The compound of formula (II) (1486 g, 2.1 mol) is loaded into a 10 Lreactor containing N,N-dimethylacetamide (1.7 L) and4-dimethylaminopyridine (12.9 g) is then added thereto. Acetic anhydride(0.9 kg, 8.82 mol) is dripped therein over about 1 hour keeping thetemperature below 30° C. The reaction mixture is stirred at roomtemperature for 20 hours, and then diluted with 96% ethanol (7.5 L). Theprecipitate is filtered, washed with 96% ethanol (2×1 L) and dried togive the compound of the title (1715 g, 1.96 mol).

Yield: 94% The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with theindicated structure.

EXAMPLE 4 Preparation of(S)-N,N′-bis[2-acetyloxy-1-[(acetyloxymethyl]ethyl]-5-[(2-acetyloxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide(IV): —R is a group B wherein R₃ is methyl)

The compound prepared in Example 3 (11 g, 12.6 mmol) is dissolved inN,N-dimetylacetamide (200 mL) containing gaseous HCl (0.055 g, 1.5 mmol)and the solution is maintained at a temperature comprised between 15 and17° C. (S)-2-(Acetyloxy)propanoyl chloride (4.75 g, 31.5 mmol) isdripped therein over 30 min. and the obtained reaction mixture isstirred at 23° C. for 20 hours. The solvent is then evaporated undervacuum and the oily residue is taken up with 4% aq. NaHCO₃ (250 mL). Theobtained precipitate is recovered by filtration, washed and dried toyield the compound of the title (9.9 g, 10 mmol).

Yield: 80% The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with theindicated structure.

EXAMPLE 5 Preparation of(S)-N,N′-bis(2,2-dimethyl-1,3-dioxan-5-yl)-5-[(2-acetyloxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide((IV): —R=a group A wherein R₁ and R₂ are methyl)

The compound prepared in Example 1 (15 g, 19 mmol) is dissolved inN,N-dimethylacetamide (80 mL) containing HCl gas (0.073 g, 2 mmol).(S)-2-(Acetyloxy)propanoyl chloride (8 g, 53 mmol) is dripped over 30min into the obtained solution cooled to 15° C. After two hours at thesame temperature, the reaction mixture is allowed to warm up to roomtemperature and stirred for additional 12 hours. The solvent is thenevaporated under vacuum and the residue is taken up with 4% NaHCO₃ (130mL). The solid obtained is filtered, washed and dried to give thecompound of the title (14 g, 15.6 mmol).

Yield: 82% The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with theindicated structure.

EXAMPLE 6 Preparation of(S)-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide(I)

(S)-N,N′-Bis[2-acetyloxy-1-[(acetyloxy)methyl]ethyl]-5-[(2-acetyloxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide(4.9 g, 5 mmol) prepared in Example 4 is admixed with deionized water(30 mL) and methanol (30 mL). The suspension is warmed to 50° C., then 2M NaOH (12.8 mL) is dripped therein over a period of 4 hours, keepingthe pH of the mixture in the range of from 0 to 11. The solution ispurified on ion exchange resins columns and the neutral eluate thusobtained is concentrated under vacuum and the residue is crystallizedfrom ethanol to give the compound of the title (2.8 g, 3.6 mmol)

Yield: 72%.

[α]₄₃₆²⁰ = −5.15(40 %  H₂O)The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with the indicatedstructure.

EXAMPLE 7 Alternative Preparation of(S)-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide(I)

0.2 M HCl (15 mL) is added to a solution of(S)-N,N′-bis(2,2-dimethyl-1,3-dioxan-5-yl)-5-[(2-acetyloxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide(9 g, 10 mmol) prepared as described in the Example 5, in methanol (60mL), and the obtained mixture is stirred at 50° C. for 2 hours, and thencooled to 40° C. 1 M NaOH (14 mL) is then dripped therein over a periodof 2 hours to keep the pH between 10.5 and 11.

After two hours, the reaction mixture is cooled to room temperature andpurified on ionic exchange resins. The neutral eluate thus obtained, isconcentrated and the residue obtained is crystallized from ethanol (80mL). The solid is filtered and dried to give the compound of the title(I) (7 g, 9 mmol).

Yield: 90% The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with theindicated structure.

EXAMPLE 8 Alternative Preparation of(S)-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide(I)

5-Amino-N,N′-bis(2,2-dimethyl-1,3-dioxan-5-yl)-2,4,6-triiodo-1,3-benzenedicarboxamideprepared as in Example 1, is reacted as described in Example 5. The(S)-N,N′-bis(2,2-dimethyl-1,3-dioxan-5-yl)-5-[(2-acetyloxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamideobtained from the reaction is not isolated, but directly deprotectedaccording to the method described in Example 7 above to give thecompound of the title.

Yield: 74%. The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with theindicated structure.

EXAMPLE 9 Alternative Preparation of(S)-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide(I)

(S)-2-(Acetyloxy)propanoyl chloride (16.5 g, 110 mmol) is added, over aperiod of 20 min, to a stirred solution ofN,N′-bis[2-acetyloxy-1-[(acetyloxy)methyl]ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide(53.3 g, 61.1 mmol) in N,N-dimethylacetamide (75 mL) while keeping thetemperature of the reaction mixture below 30° C. An additional amount of(S)-2-(acetyloxy)propanoyl chloride (0.9 g, 6.0 mmol) is added after 24and 30 hours and the reaction mixture is stirred at the same temperaturefor further 15 hours. The reaction mixture is then concentrated to halfvolume and diluted with a 1:1 mixture of water/methanol (360 mL). Theresulting suspension is heated to 45° C. and 2 M NaOH (225 mL, 450 mmol)is added over 30 min. After 2 h the hydrolysis is complete, the solutionis concentrated to half volume, extracted with CH₂Cl₂ (6×100 mL) andloaded onto two ion exchange resin columns (Dowex® C350, H⁺ form, 200mL; Relite® MG1, OH⁻ form, 160 mL) that are eluted with water. Theeluate is evaporated and the solid residue (49 g) thus obtained iscrystallized from ethanol (450 mL). The recovered solid (40.5 g) isdissolved in H₂O (400 mL) and the solution loaded onto an Amberlite®XAD-16.00 resin column (160 mL) that is eluted with water. The eluate isevaporated and the residue dried to afford Iopamidol (40.0 g, 51.5 mmol)as a white solid.

Yield: 84%

[α]₄₃₆²⁰ = −5.17(40 %  H₂O)

EXAMPLE 10 Alternative Preparation of(S)-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide(I)

(S)-2-(Acetyloxy)propanoyl chloride (16.5 g, 110 mmol) is added, over 20min, to a stirred solution ofN,N′-bis[2-acetyloxy-1-[(acetyloxy)methyl]ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide(53.3 g, 61.1 mmol) in N,N-dimethylacetamide (75 mL) while keeping thetemperature of the reaction mixture below 30° C. A further amount of(S)-2-(acetyloxy)propanoyl chloride (0.9 g, 6.0 mmol) is added after 24and 30 hours and the reaction mixture is stirred at the same temperaturefor additional 15 hours. 5 M NaOH (90 mL, 450 mmol) is dripped over aperiod of 2 hours into the reaction mixture vigorously stirred at 45° C.After two hours the mixture is concentrated under vacuum andreintegrated with additional N,N-dimethylacetamide (200 mL). After twohours at room temperature the resulting suspension is filtered and thesolid washed with N,N-dimethylacetamide (2×20 mL). The mother liquors,combined with the washings, are concentrated to an oily residue, whichis diluted with water (200 mL) and nanofiltered. The retentate is loadedonto an Amberlite® XAD-16.00 resin column (160 mL) that is eluted withwater. The eluate is concentrated and loaded onto two ion exchange resincolumns (Dowex® C350 15 mL, Relite® MG1 10 mL). The eluate isconcentrated and the solid residue is crystallized from ethanol toafford Iopamidol (41.2 g, 53 mmol).

Yield: 87%

[α]₄₃₆²⁰ = −5.19(40 %  H₂O)

1. Process for the preparation of(S)-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamideof formula (I)

starting from the compound of formula (II)

which process comprises a) reacting the compound of formula (II) with asuitable protecting agent, to give a compound of formula (III)

wherein —R is a group of formula A or B

wherein R₁ is a hydrogen atom, a C₁÷C₄ straight or branched alkyl groupor a C₁÷C₄ straight or branched alkoxy group, R₂ is hydrogen, a C₁÷C₄straight or branched alkyl group or a C₁÷C₄ straight or branched alkoxygroup and R₃ is a C₁÷C₄ straight or branched alkyl group, atrifluoromethyl or a trichloromethyl group; b) acylating the amino groupin position 5 of the intermediate compound of formula (III), by reactionwith a (S)-2-(acetyloxy)propanoyl chloride to give a compound of formula(IV)

wherein R is as defined above; and c) removing all the acyl groupspresent in the compound of formula (IV) under basic conditions, withprior cleavage of the cyclic protection under acidic conditions when Ris a group of formula A.
 2. The process of claim 1 wherein, in theintermediate compound of formula (III) obtained in step a), —R is agroup A.
 3. The process of claim 2 wherein R₁ and R₂ are C₁÷C₄ straightalkyl groups.
 4. The process of claim 1 wherein, in the intermediatecompound of formula (III) obtained in step a), —R is a group B.
 5. Theprocess of claim 4 wherein R₃ is a C₁÷C₄ straight alkyl group.
 6. Theprocess of claim 2 wherein step a) is carried out by reacting thecompound of formula (II) with at least 2 mol per mol of compound (II) ofa compound selected from di-(C₁–C₄)alkoxy-methane, aldehydes and ketonesof formula R₁COR₂ (possibly in the corresponding acetal or ketal relatedforms) wherein R₁ is a hydrogen atom or a C₁÷C₄ straight or branchedalkyl group and R₂ is a C₁÷C₄ straight or branched alkyl group andorthoesters R₁C(R₂)₃ when at least R₂ is an alkoxy group, in thepresence of from about 0.1 to about 2 mol of an acid per mol of compoundof formula (II).
 7. The process of claim 4 wherein step a) is carriedout by reacting the compound of formula (II) with at least four mol ofan anhydride (R₃CO)₂O per mol of compound of formula (II) in thepresence of catalytic amounts of 4-(dimethylamino)pyridine in a dipolaraprotic organic solvent.
 8. The process of claim 1 wherein the acylationof step b) is carried out by reacting the compounds (III) with at leastone mol of (S)-2-(acetyloxy)-propanoyl chloride in an inert dipolaraprotic solvent and in presence of from about 0.1 to about 0.4 mol permol of product of formula (III) of an acid.
 9. The process of claim 2wherein removal of the acyl group of the compound of formula (IV)wherein —R is a group of formula A under basic conditions according tostep c) is carried out in water or in a mixture of water and an organicsolvent miscible therewith, keeping the pH of the reaction mixturebetween 10 and 11 by the addition of a strong inorganic base, and ispreceded by cleavage of the cyclic protections of the carboxamidohydroxy groups under acidic conditions.
 10. The process of claim 4wherein removal of all the acyl groups under basic conditions of step c)is carried out in water or in a mixture of water and an organic solventmiscible therewith keeping the pH of the reaction mixture between 10 and11 by the addition of a strong inorganic base.
 11. The process of claim10 wherein the organic solvent miscible with water is selected from thegroup consisting of C₁÷C₄ straight or branched alkanols and the dipolaraprotic organic solvents and the pH of the reaction mixture ismaintained between 10 and 11 by the addition of an aqueous solution ofNaOH or KOH.